Long noncoding RNA LINC01842 enhances disulfidptosis resistance and promotes glioma progression via IQGAP1

Long noncoding RNA LINC01842 enhances disulfidptosis resistance and promotes glioma progression via IQGAP1 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Long noncoding RNA LINC01842 enhances disulfidptosis resistance and promotes glioma progression via IQGAP1 Fuguang Zhang, Heng Wang, Weiqian Zheng, Dinghao Wang, Chuangnan Yan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4192532/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Long non-coding RNA (lncRNA) is widely present in cells and is demonstrated to play vital roles in the development and progression of glioma. However, the biological roles and function mechanisms of LINC01842 in glioma are not yet clear. This study aims to elucidate the potential role of LINC01842 in glioma, specifically its association with disulfidptosis. Methods: We obtained sequencing data from The Cancer Gene Atlas (TCGA). Correction analysis was applied to select disulfidptosis-related lncRNAs (DRLs). Prognosis-associated DRLs were identified by least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM). Receiver operating characteristic (ROC) curve and multivariate Cox regression analyses were used to screen our target gene LINC01842. Subsequently, expression of LINC01842, IQGAP1and SLC7A11 in glioma cell lines was detected by real-time quantitative polymerase chain reaction (qPCR). Additionally, CCK8 experiments and wound healing assays were performed to assess cell viability, migration, and invasion. Finally, online database predictions were used to validate the drug sensitivity of glioma. Results: LINC01842 was more highly expressed in high-grade gliomas, and glioma patients with high expression level of LINC01842 had poorer survival. Additionally, tumor cells with high expression of LINC01842 exhibited stronger tumor characteristics, such as migratory and invasive abilities, as well as tolerance to disulfidptosis. Furthermore, strong binding between LINC01842 and the disulfidptosis-related gene IQGAP1 could be predicted, and their expression levels were positively correlated. Ultimately, drug sensitivity analysis suggested glioma patients with high expression level of LINC01842 were sensitive to eight drugs. Conclusion: High expression of LINC01842 is associated with poor prognosis in glioma patients. By interacting with IQGAP1, the resistance to disulfidptosis of LINC0182 was stronger in glioma, which promotes the progression of glioma. Eight discovered sensitive drugs provided important clues for personalized treatment of glioma. glioma disulfidptosis LINC01842 IQGAP1 SLC7A11 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Glioma is a malignant brain tumor with highly invasive and treatment-resistant properties (Venkataramani V et al., 2022 ). Gliomas are characterized by the formation of abundant new blood vessels and unusual vascular structures, which often lead to resistance against conventional treatments, such as radiotherapy and chemotherapy, resulting in tumor recurrence and poor prognosis (Ahir BK et al., 2020 ; Yang H et al., 2022 ; Ma W et al., 2021 ). Traditional treatment options, such as surgical resection, radiotherapy, and chemotherapy, can alleviate symptoms and control tumor growth to some extent (Su X et al., 2022 ; Kim Y et al., 2023 ; Tsien CI et al., 2023 ). However, not all patients experience ideal treatment outcomes with these approaches (Wang C et al., 2023 ). Therefore, it is crucial to explore new therapeutic strategies to improve the treatment effectiveness of glioma. Recent studies have revealed that in cells with high expression of the SLC7A11 gene, when they encounter glucose starvation, there is an abnormal accumulation of cysteine and other disulfides within the cells, leading to disulfide stress (Liu X et al., 2023 ). This process triggers an increase in the content of disulfide bonds in the actin cytoskeleton, causing contraction of actin filaments and disruption of the cytoskeletal structure, ultimately resulting in cell death (Liu X et al., 2023 ). This cell death pathway is known as disulfidptosis, which is distinct from apoptosis and ferroptosis (Zheng T et al., 2023 ). Currently, research on disulfidptosis is still in its early stages and mainly focuses on a few types of tumors. For instance, studies have found that multiple disulfidptosis-related genes, such as LRPPRC, OXSM, GYS1, and SLC7A11, are associated with prognosis in patients with renal clear cell carcinoma (Zhang D et al., 2023 ). Additionally, research by Zhang et al. suggests that disulfidptosis-related genes, such as KIF20A, G6PD, SLC7A11, and SLC2A1, play a role in the development of liver cancer (Zhang C et al., 2023 ). Moreover, it has been reported that a combination of disulfidptosis-related genes, such as EPHX1, LDHA, SHC1, MYO6, and TLE1, can predict the clinical prognosis of patients with lung adenocarcinoma (He D et al., 2023 ). Although the relationship between disulfidptosis and glioma progression has not been reported, the aggressive proliferative nature of glioma leads to inadequate blood supply to the tumor tissue (Truong D et al., 2019 ; Kim Y et al., 2023 ), making the tumor cells susceptible to glucose starvation (Chisari A et al., 2021 ; Teramoto K et al., 2019). As mentioned above, glucose starvation triggers an increase in the content of disulfide bonds in cell, causing contraction of actin filaments and disruption of the cytoskeletal structure, ultimately resulting in disulfidptosis (Liu X et al., 2023 ). This suggests a potential, as yet unknown connection between glioma development and disulfidptosis. However, further research is needed to explore their relationship. Long non-coding RNA (lncRNA) is a class of RNA molecules that are widely present in cells (Ahmadpour ST et al., 2023 ; Hasenson SE et al., 2022 ). They are usually longer than 200 nucleotides and do unable to transform proteins (Nojima T et al., 2022). Recent studies have shown that lncRNAs play a significant role in the formation and development of glioma through gene regulation and epigenetic modifications (Li Z et al., 2021 ). For example, high expression of lncRNA HOTAIR in high-grade gliomas is associated with lower survival rates (Wang X et al., 2022 ). Additionally, it has been reported that lncRNA GAS5 inhibits glioma maintenance through a miR-196a-5p/FOXO1 feedback loop (Zhao X et al., 2017 ). Moreover, FOXM1-AS has been found to facilitate the interaction between ALKBH5 and newly transcribed FOXM1, leading to the activation and progression of glioma (Zhang S et al., 2017 ). However, the regulation of lncRNAs in disulfidptosis in glioma is not yet clear. In this study, we identified a 785 nt long non-coding RNA1842 (LINC01842, ENSG00000267147), that was highly expressed in high-grade gliomas tissues and patients with high expression levels of LINC01842 had worse survival prognosis. Besides, tumor cells with high expression of LINC01842 have stronger tumor characteristics, such as migration and disulfidptosis resistance. Furthermore, In our study, we revealed that LINC01842 exerted its disulfidptosis resistance through interaction with IQGAP1.Our research findings provide evidence for the involvement of LINC01842 in glioma and offer new insights for personalized and precise treatment strategies for this disease. Materials and methods Acquisition of datasets and disulfidptosis-related lncRNA The RNA-seq transcriptome data for glioblastoma (GBM) and lower grade glioma (LGG) were downloaded from The Cancer Genome Atlas (TCGA) ( https://portal.gdc.cancer.gov/ ), and all data was normalized to TPM (transcripts per million) value. In addition, the clinical information involving age, sex and grade was collected. Samples missing survival information were excluded. In all, a total of 709 samples were filtered for the study. Fifteen disulfidptosis-related genes (DRGs) were included based on a previous study: FLNA, FLNB, MYH9, TLN1, ACTB, MYL6, MYH10, CAPZB, DSTN, IQGAP1, ACTN4, PDLIM1, CD2AP, INF2, SLC7A11 (Wang T et al., 2023 ). Using these target genes, we screened 545 disulfidptosis-related lncRNAs (DRLs) by person correction analysis. Correlations with a correlation coefficient absolute value of > 0.5, and corresponding to a p-value < 0.05 were considered eligible. Identification of LINC01842 as a key prognosis-related gene Firstly, we obtained 331 prognostic DRLs by using univariate cox regression analysis. Secondly, the LASSO and SVM-RFE algorithms were used to choose the putative prognostic DRLs. Six common lncRNAs were filtered by integrated analysis of two algorithms. Thirdly, five lncRNAs were identified as independent prognosis lncRNAs. Among the genes, AL592295.6 was a protective gene, whereas AC064875.1, AC131097.3, MIR155HG, LINC01842 were risk genes. Subsequently, the R package “pROC” was leveraged to perform a ROC curve. The area under the ROC curve of the LINC01842 was 0.7821. Thus, we selected LINC01842 for further analysis. Drug response prediction Pharmacogenomic data from Genomics of Drug Sensitivity in Cancer (GDSC) includes the therapeutic sensitivity of cancer cells and molecular markers of drug response (Yang W et al., 2013 ). The R package “oncoPredict” was used to calculate the half maximal inhibitory concentration (IC50) value, which is an indicator of drug sensitivity (Maeser D et al., 2021 ). Cell culture Two human glioma cell lines (U251 and LN229) were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Both cell lines were cultured in Dulbecco’s modified Eagle’s medium (DMEM, Gibco BRL, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (Gibco BRL, Grand Island, NY, USA) and antibiotics (100 U/mL penicillin and 100 µg/mL streptomycin, Gibco, Grand Island, NY, and Scotland, UK) at 37°C in a humidified atmosphere containing 5% CO2. Cell counting kit-8 (CCK8) assay Cells of each group were inoculated at a density of 1×10 4 cells/well in a 96-well plate, with 6 replicate wells for each group. After 24 hours, cell viability was measured by adding 10 µL of CCK8 reagent (Beyotime, Jiangsu, China)/well and incubating for 3 hours in a CO2 incubator. Cell viability was determined at the wavelength of 450 nm. Quantitative real-time PCR (qPCR) Quantitative real-time polymerase chain reaction (qRT-PCR) was performed. Total RNA was extracted from human tissues and cultured cells using TRIzol reagent (Takara, Shiga, Japan). Subsequently, cDNA was generated using a reverse transcription kit (Takara, Shiga, Japan), and gene expression was quantified using a SYBR Green PCR kit (Takara, Shiga, Japan) according to the manufacturer’s instructions. The primer sequences are listed in Table S1 . Glucose deprivation We seeded glioma cells onto a 6-well cell culture plate (Corning, NY, USA) and allowed the cells to grow to approximately 90% confluence. The cell culture media was then replaced with glucose-free DMEM. After continuous cultivation for 24 hours, RNA extraction was performed for further analysis. Wound healing assay To assess the migration and invasion of glioma cells in vitro, we performed a wound healing assay. Glioma cells were seeded onto a 6-well cell culture plate (Corning, NY, USA). Using a 200 µL pipette tip, a vertical scratch was made at the center of each well. The cells were then cultured in DMEM media without fetal bovine serum (FBS) for 24 hours. Images were captured under a 10x microscope objective. The gap area was measured using ImageJ software’s ruler tool. Changes in the gap area were calculated and analyzed using statistical methods. Statistical analysis Data are presented as mean ± standard error of the mean (SEM). Statistical analysis was performed using R language (version 3.5), SPSS 25.0 software (SPSS Inc., Chicago, Illinois) or GraphPad Prism 7 (GraphPad software, La Jolla, CA). The R package “survminer” was used to estimate OS between two groups using Kaplan-Meier survival plots. Cox regression of survival analysis was implemented by the R package “survival”. Related R packages, including “ggplot2” and “ggpubr”, were used to visualize the data. Differences with P < 0.05 were considered statistically significant. Results Identification of disulfidptosis-related lncRNAs using TCGA The workflow in the current study is illustrated in Fig. 1 . To explore the role of lncRNAs associated with disulfidptosis in glioma, we first screened 545 disulfidptosis-related lncRNAs (DRLs) by person correction analysis and constructed a gene network map (Fig. 2 A). An absolute value of correlation coefficients > 0.5 corresponding to a P < 0.05 was considered eligible for consideration. Next, we obtained RNA-seq data from 709 samples in TCGA. Considering that traditional Cox regression analysis often ignores multicollinearity between variables when dealing with multiple gene variables, which may lead to inaccurate results, we used LASSO regression analysis to identify lncRNAs associated with prognosis. The results showed that 25 lncRNAs were significantly correlated with prognosis (cor_thred = 0.5, p value_thred = 0.001) (Fig. 2 B). We performed 10-fold cross-validation to determine the optimal value of the penalty parameter (Fig. 2 C). Additionally, we used the support vector machine recursive feature elimination (SVM-RFE) algorithm for machine learning feature selection, and identified 11 prognosis-related lncRNAs (Fig. 2 D). We then performed Venn diagram analysis on the results of these two machine learning algorithms to obtain their intersection. Last, we selected 6 lncRNAs, LINC01842, AL592295.6, AC131097.3, MIR155HG, CYTOR, and AC064875.1, as prognostic risk factors for glioma (Fig. 2 E). To further explore the independent prognostic impact of each lncRNA, we conducted receiver operating characteristic (ROC) curve analysis and stepwise regression multivariate Cox regression analysis. The results showed that their predictive efficacy for glioma prognosis was high, with AUC values greater than 0.7 (AL592295.6 = 0.77, AC131097.3 = 0.785, MIR155HG = 0.763, LINC01842 = 0.7821, CYTOR = 0.79102, AC064875.1 = 0.76075) (Fig. 2 F). However, only 5 lncRNAs served as independent prognostic factors for glioma: LINC01842, AL592295.6, AC131097.3, MIR155HG, and AC064875.1(Fig. 2 G). Particularly noteworthy is that LINC01842 is considered an oncogene, and it has the highest hazard ratio and a highly significant p-value (HR = 1.377, P < 0.001 ), indicating that LINC01842 may be closely associated with poor prognosis in glioma patients. Therefore, we further investigated and analyzed LINC01842 in detail. Age and malignancy grade of glioma may affect the expression of LINC01842 To study the association between LINC01842 and the prognosis of glioma, we analyzed the expression of this gene in different subgroups, including gender, age (< 60 years or ≥ 60 years), and malignancy grade of glioma (WHO: G2, G3, G4). We found that expression of LINC01842 did not differ significantly between genders ( P = 0.7935 ) (Fig. 3 A), but there were significant differences in its expression levels among different age groups and malignancy grades of glioma ( P < 0.001 ). Notably, LINC01842 expression was higher in patients over 60 years of age and those with high-grade gliomas (Fig. 3 B, C). These results suggest that the age and tumor malignancy of patients may affect the expression of LINC01842. Additionally, other studies have reported that the expression of LINC01842 is higher in lymph node metastasis patients than in non-metastasis patients with non-small cell lung cancer (Wang X et al., 2019 ), which is consistent with our findings. Glioma patients with high expression of LINC01842 exhibit poorer clinical prognosis To eliminate the interference of age and tumor malignancy grade on LINC01842expression level, we grouped patients based on high or low expression levels of LINC01842 under different conditions of gender, age, and tumor malignancy grade, and analyzed the impact of LINC01842 on the survival rate of glioma patients. Interestingly, we found a consistent phenomenon across different gender, age, and tumor malignancy grade conditions: patients with high expression levels of LINC01842 had worse survival prognosis (Fig. 4 ). This suggests that although age and tumor malignancy grade can affect the expression level of LINC01842, LINC01842 is the major factor affecting the prognosis of glioma. Therefore, there may be a close association between LINC01842 and the occurrence and development of glioma. Biological information of LINC01842 To investigate the relationship between LINC01842 and the development of glioma, we first analyzed the genomic information of LINC01842 using the UCSC Genome database ( https://genome.ucsc.edu/ ). We found that LINC01842 is a conserved and abundant lncRNA, currently annotated as LINC01842 in humans. It is located on chromosome 19p13.12 on the coding strand. The gene sequence can produce two transcripts: NR_134916.1 and NR_134908.1. Additionally, high levels of regulatory element markers, such as cCREs and CpG islands, were detected for LINC01842 (Fig. 5 A). These results suggest that LINC01842 possesses enhancer activity rather than coding activity. Although genetic information is encoded in the RNA sequence, lncRNA activity depends on the RNA folding into specific secondary or tertiary structures. A well-known example is ribosomal RNA, which forms complex tertiary structures and catalyzes protein synthesis during translation (Häfner SJ et al., 2023 ). Using the lncRNA-related functionality database ( http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi ), we further analyzed the structure and function of LINC01842. The analysis revealed the presence of multiple stable stem-loop structures in LINC01842 (Fig. 5 B, C). These structures may have binding or catalytic roles with proteins. Moreover, the analysis results showed that LINC01842 is predominantly located in the cytoplasm (Fig. 5 D), suggesting that this gene may participate in gene regulation at the post-transcriptional level. For example, LUCAT1 competes for binding with miR-375 in the cytoplasm to regulate the proliferation and invasion of glioma cells (Gao YS et al., 2018 ). Furthermore, we discovered through the NONCODE database ( http://www.noncode.org/ ) that LINC01842 is primarily expressed in normal lung tissues (Fig. 5 E). However, LINC01842 is predominantly overexpressed in highly malignant tumors, such as invasive breast cancer, renal clear cell carcinoma, and lung squamous cell carcinoma (Fig. 5 F). Tumor cells with high expression of LINC01842 exhibit more invasive To further investigate the mechanism of LINC01842 in the development of tumors, we cultured two glioma cell lines (U251 and LN229) and determined the expression level of LINC01842. Compared to LN229 cells, LINC01842 was expressed at a higher level in U251 cells (Fig. 6 B). Based on our bioinformatics analysis and prior studies (Wang X et al., 2019 ), tumor cells with high expression of LINC01842 may have more invasive. Furthermore, to compare the invasion ability of U251 and LN229 cell lines, we performed wound healing assays on the two cell lines. a U251 cells had a faster wound healing rate (Fig. 6 A, C), suggesting that U251 cells had greater migration abilities. Additionally, according to previous reports (Liu X et al., 2023 ), we induced cell death in both cell lines by treating them with glucose deprivation for 24 hours. We found that U251 cells had higher cell viability than LN229 cells (Fig. 6 D, E), and the expression levels of SLC7A11, a critical gene in disulfidptosis (Liu X et al., 2023 ), were increased in both cell lines after treatment (Fig. 7 D, H). This may indicate that U251 cells have a stronger tolerance to disulfidptosis. In summary, our experimental data and bioinformatics analysis mutually support the notion that tumor cells with high expression of LINC01842 are more invasive, such as migration and disulfidptosis resistance. These results show that LINC01842 may be positively correlated with the malignancy of tumors. Glioma cells with high expression of IQGAP1 have stronger disulfidptosis tolerance According to previous reports in the literature, when cells are deprived of glucose, cytoskeleton collapse and plasma membrane separation occur, ultimately leading to cell death, known as disulfidptosis (Liu X et al., 2023 ). In addition, LINC01842 was predicted to be associated with IQGAP1, an intracellular actin-binding protein that can maintain cytoskeleton stability and regulate various cellular activities by promoting intracellular signal transduction (Thines L et al., 2023 ). Therefore, we focused on the role of IQGAP1 in glioma. In our study, we found that expression of IQGAP1 was higher in U251 cells than in LN229 cells (Fig. 7 J). Online immunohistochemical analysis ( www.proteinatlas.org ) also showed that the expression of IQGAP1 was higher in tissues with high-grade gliomas and lower in tissues with low-grade gliomas (Fig. 7 I). This indicates that the expression level of IQGAP1 may be related to the malignant degree of tumors. Our experimental results (Fig. 6 A, C, D, E) are consistent with the study by Zhang et al., which showed that high expression of IQGAP1 enhances the migration and invasion of neuroglioma (Zhang Q et al., 2019). In addition, we induced a cell model of disulfidptosis by subjecting the above two cell lines to glucose deprivation for 24 hours. After treatment, the expression levels of IQGAP1 increased in both cell lines (Fig. 7 E, F). Interestingly, the expression level of IQGAP1 in U251 cells was consistently higher than that in LN229 cells before and after glucose deprivation (Fig. 7 G), and the expression of LINC01842 also showed consistent changes with IQGAP1 (Fig. 7 A, B, C). Combined with the stronger tolerance of U251 cells compared with LN229 cells, we postulate that U251 cells may exhibit disulfidptosis resistance by maintaining cytoskeleton stability by overexpressing IQGAP1. In summary, our data indicate that glioma cells with high expression of IQGAP1 have stronger disulfidptosis tolerance. LINC01842 participates in disulfidptosis through IQGAP1 To further investigate the cellular regulatory mechanisms of LINC01842, IQGAP1, and SLC7A11, we conducted a correlation analysis between them by their expression levels. The results revealed a positive correlation between the expression levels of LINC01842 and IQGAP1 (R = 0.51, P < 0.001) (Fig. 8 A), but no significant correlation between LINC01842 and SLC7A11 expression levels (R = 0.07, P = 0.08) (Fig. 8 B). This suggests that LINC01842 may primarily influence the expression of IQGAP1, leading to the development of resistance to disulfidptosis. To explore the potential interaction between LINC01842 and IQGAP1, we utilized an online analysis tool ( http://service.tartaglialab.com/ ) to predict their potential binding sites based on their secondary structure, hydrogen bonding, and van der Waals interactions. The results demonstrated a strong binding capability between LINC01842 and IQGAP1 (prediction using RF classifier = 0.7, prediction using SVM classifier = 0.78) (Fig. 8 C). This further supports the hypothesis that LINC01842 may promote resistance to disulfidptosis through its interaction with IQGAP1. Identification of potential drugs targeting LINC01842 Given that chemotherapy is also an effective method for the treatment of glioma (Le Rhun E et al., 2019 ), it has important clinical application value and prospects. Therefore, using the oncoPredict algorithm, we aimed to identify potential drugs that target LINC01842 and predict drug sensitivity in glioma patients. The results showed that there was a negative correlation between LINC01842 and IC50 values of 8 drugs (Fig. 9 A). We selected the top 5 drugs with the strongest correlation to LINC01842 for analysis. These drugs, namely entospletinib (targeting drug, Syk inhibitor), AZD2014 (targeting drug, mTOR inhibitor), PLX-4720 (targeting drug, B-Raf inhibitor), rapamycin (targeting drug, mTOR inhibitor) and SCH772984 (targeting drug, ERK inhibitor), exhibited meaningfully lower IC50 values in the high-LINC01842 group than the low-LINC01842 group, which suggests that these drugs may bring greater benefits to patients in the high-LINC01842 group (Fig. 9 B–F). Discussion Glioma is a molecularly heterogeneous malignant tumor (Gusyatiner O et al., 2018), and the current main drug used for its treatment is TMZ, but its efficacy is limited (Corrigenda et al., 2017). Therefore, it is crucial to identify key biomarkers and therapeutic targets that influence prognosis in order to improve the clinical outcomes of glioma patients. In addition, disulfidptosis, as a mode of cell death similar to other cell death modes, plays an important role in the development of various types of tumors. For example, ferroptosis assists in overcoming gemcitabine resistance in pancreatic cancer (Kim MJ et al., 2023 ), and pyroptosis affects all stages of tumor carcinogenesis (Tan Y et al., 2021 ). Studies have suggested that disulfidptosis-related genes, such as POU5F1 and CTSE, may be potential targets for treating bladder cancer (Chen H et al., 2023 ). Moreover, the disulfidptosis-related gene G6PD can inhibit the proliferation of lung cancer cells (Qi C et al., 2023 ). Therefore, we postulated that disulfidptosis-related genes (DRGs) may play a role in the occurrence and prognosis of glioma. Long non-coding RNA (lncRNA) has been confirmed to play an important role in the prognosis of glioma and may serve as a potential molecular target for glioma treatment. Some studies have found that lncRNA NEAT1 promotes the development of glioma by stabilizing PGK1, and high expression of NEAT1 is associated with poor overall survival in patients (Liang J et al., 2022 ). In addition, mitochondrial ferritin promotes tumor occurrence and angiogenesis in glioma through the expression of long non-coding RNA SNHG1 (Mi S et al., 2020 ). However, the regulatory mechanism of disulfidptosis in glioma and its relationship with lncRNA still remain unclear. Therefore, it is necessary to focus on the interaction between disulfidptosis and lncRNA in order to identify effective prognostic markers. First, we predicted lncRNAs associated with disulfidptosis based on 14 ferroptosis-related genes (DRGs), and constructed a network of disulfidptosis-related genes. Then, we obtained RNA-seq data of glioma tissue from TCGA and used a series of bioinformatics analyses to screen our target gene LINC01842. LINC01842 was found to be an oncogene, as it had the highest hazard ratio and a significant p-value, suggesting a strong association with poor prognosis in glioma patients. Currently, there is limited research on LINC01842 in the context of cancer treatment. To our knowledge, there are only two reported studies on LINC01842. One study constructed a competing endogenous RNA (ceRNA) network centered around LINC01842 and other long non-coding RNAs to guide the diagnosis and prognosis of lung adenocarcinoma (Wang X et al., 2019 ). Another study found a correlation between LINC01842 and tumor immunity as well as clinical prognosis in glioma (Chen F et al., 2022 ). Our study also revealed that glioma patients with high expression of LINC01842 have worse clinical outcomes, and glioma cell lines with high expression of LINC01842 exhibit stronger tumor characteristics, such as invasiveness, proliferation, and resistance to disulfidptosis. IQ motif containing GTPase activating protein 1 (IQGAP1) is a large, widely expressed protein with a size of 190 kDa (Weissbach L et al., 1994 ). IQGAP1 belongs to the IQGAP protein family and is evolutionarily conserved in eukaryotes (Abel AM et al., 2015 ; Hedman AC et al., 2015 ). It was first identified in 1994 and initially believed to be a GTPase activating protein (GAP) that promotes signal termination based on its sequence similarity to other known GAPs (Weissbach L et al., 1994 ). However, subsequent studies revealed that IQGAP1 does not shut down signals but rather stabilizes the activity of binding partners such as RAC1 and CDC42 by inhibiting their intrinsic GTPase activity (Hart MJ et al., 1996 ). Research has demonstrated that this protein is involved in various biological activities, including cell cytoskeleton dynamics, cell-cell adhesion, cell motility/invasion, and cell proliferation (Tanos BE et al., 2016; Smith JM et al., 2015 ; Thines L et al., 2023 ; Rotoli D et al., 2019 ). Our study found that there is a binding site between LINC01842 and IQGAP1, and their expression levels are positively correlated. To further investigate the relationship between LINC01842 and IQGAP1, we conducted in vitro experiments such as cell scratch assays, cell viability assays, and glucose deprivation, using two glioma cell lines (U251 and LN229). The results showed that the cell line with higher expression of LINC01842 (U251 cells) also exhibited higher expression of IQGAP1 and demonstrated increased resistance to disulfidptosis. Therefore, we propose that U251 cells may enhance their resistance to disulfidptosis by maintaining cytoskeletal stability through the upregulation of IQGAP1. In addition, we also predicted the drug sensitivity of glioma patients and found that patients with high expression of LINC01842 should be sensitive to entospletinib, AZD2014, PLX-4720, rapamycin and SCH772984. This evidence may further guide the chemotherapy and targeted therapy of glioma. It should be noted that we did not choose to conduct in vitro experiments on normal astrocytes for multiple reasons. Firstly, our study focused mainly on investigating the effect of LINC01842 on tumor characteristics of glioma cells, such as invasion, proliferation, and resistance to disulfidptosis. Secondly, in the process of screening LINC01842, we did not analyze the expression levels of this gene in normal astrocytes, but rather compared its expression levels in glioma samples of different degrees of malignancy. Finally, we found that there were expression differences of LINC01842 between the U251 and LN229 glioma cell lines. Therefore, using these two cell lines for in vitro experiments provides us with a better understanding of the role of LINC01842 in glioma. However, our study still has certain limitations: (1) most of the data are derived from the public database TCGA and lack sufficient experimental evidence and animal models to validate the results, which may cause potential selection bias, (2) the sensitivity of glioma tissue to chemotherapy and targeted drugs is yet to be verified, and (3) the specific mechanism of disulfidptosis remains relatively mysterious and deserves further investigation. Therefore, we will carry out multiple studies in the future to further explore the molecular relationship between LINC01842 and disulfidptosis in glioma. Conclusion In summary, our study showed that LINC01842 was able to promote tumor growth and metastasis of glioma both in bioinformatics analysis and in vitro experiments. Mechanistically, we demonstrated that LINC01842 could interact with IQGAP1 to promote resistance to disulfidptosis of glioma. Moreover, using OncoPredict, we found that glioma patients with high expression level of LINC01842 were sensitive to eight drugs. Declarations Author Contribution FZ and HW contributed to the study design and wrote the article. WC and DW conducted the literature search. CY and SC acquired the data. HX revised the article and gave the fnal approval of the version to be submitted. Ethical Statement ： This declaration is not applicable. Funding Statement ： The study was funded by two grants : teaching Reform Research Program of Clinical Teaching Base of Guangdong Province, 〔2022〕21-2021JD066 and the Medical Scientific Research Foundation of Guangdong Province of China, Grant No. A2022176. Data availability statement: The data that support the findings of this study are available on request from the corresponding author, Hongwu Xu，upon reasonable request. 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Dev Cell 58(17):1593–1609e9 Gao YS, Liu XZ, Zhang YG, Liu XJ, Li LZ (2018) Knockdown of Long Noncoding RNA LUCAT1 Inhibits Cell Viability and Invasion by Regulating miR-375 in Glioma. Oncol Res 26(2):307–313 Thines L, Roushar FJ, Hedman AC, Sacks DB (2023) The IQGAP scaffolds: Critical nodes bridging receptor activation to cellular signaling. J Cell Biol 222(6):e202205062 Zhang Q, Zheng J, Wu W, Lian H, Iranzad N, Wang E, Yang L, Wang X, Jiang X (2023) TRIM56 acts through the IQGAP1-CDC42 signaling axis to promote glioma cell migration and invasion. Cell Death Dis 14(3):178 Le Rhun E, Preusser M, Roth P, Reardon DA, van den Bent M, Wen P, Reifenberger G, Weller M (2019) Molecular targeted therapy of glioma. Cancer Treat Rev 80:101896 Gusyatiner O, Hegi ME (2018) Glioma epigenetics: From subclassification to novel treatment options. Semin Cancer Biol 51:50–58 Corrigenda (2017) Neuro Oncol. ;19(12):1701. 10.1093/neuonc/nox110 . Epub 2017 Jun 27. Erratum for: Neuro Oncol. 2017;19(6):862–870 Kim MJ, Kim HS, Kang HW, Lee DE, Hong WC, Kim JH, Kim M, Cheong JH, Kim HJ, Park JS (2023) SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer. Cells 12(20):2509 Tan Y, Chen Q, Li X, Zeng Z, Xiong W, Li G, Li X, Yang J, Xiang B, Yi M (2021) Pyroptosis: a new paradigm of cell death for fighting against cancer. J Exp Clin Cancer Res 40(1):153 Chen H, Yang W, Li Y, Ma L, Ji Z (2023) Leveraging a disulfidptosis-based signature to improve the survival and drug sensitivity of bladder cancer patients. Front Immunol 14:1198878 Qi C, Ma J, Sun J, Wu X, Ding J (2023) The role of molecular subtypes and immune infiltration characteristics based on disulfidptosis-associated genes in lung adenocarcinoma. Aging 15(11):5075–5095 Liang J, Liu C, Xu D, Xie K, Li A (2022) LncRNA NEAT1 facilitates glioma progression via stabilizing PGK1. J Transl Med 20(1):80 Mi S, Du J, Liu J, Hou K, Ji H, Ma S, Ba Y, Chen L, Xie R, Hu S (2020) FtMt promotes glioma tumorigenesis and angiogenesis via lncRNA SNHG1/miR-9-5p axis. Cell Signal 75:109749 Wang X, Su R, Guo Q, Liu J, Ruan B, Wang G (2019) Competing endogenous RNA (ceRNA) hypothetic model based on comprehensive analysis of long non-coding RNA expression in lung adenocarcinoma. PeerJ 7:e8024 Chen F, Peng X, Teng Z, Long H, Wu H (2022) Identification of Prognostic LncRNAs Subtypes Predicts Prognosis and Immune Microenvironment for Glioma. Evid Based Complement Alternat Med 2022:3709823 Weissbach L, Settleman J, Kalady MF, Snijders AJ, Murthy AE, Yan YX, Bernards A (1994) Identification of a human rasGAP-related protein containing calmodulin-binding motifs. J Biol Chem 269(32):20517–20521 Abel AM, Schuldt KM, Rajasekaran K, Hwang D, Riese MJ, Rao S, Thakar MS, Malarkannan S (2015) IQGAP1: insights into the function of a molecular puppeteer. Mol Immunol 65(2):336–349 Hedman AC, Smith JM, Sacks DB (2015) The biology of IQGAP proteins: beyond the cytoskeleton. EMBO Rep 16(4):427–446 Hart MJ, Callow MG, Souza B, Polakis P (1996) IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs. EMBO J 15(12):2997–3005 Tanos BE, Yeaman C, Rodriguez-Boulan E (2018) An emerging role for IQGAP1 in tight junction control. Small GTPases 9(5):375–383 Epub 2016 Nov 23 Smith JM, Hedman AC, Sacks DB (2015) IQGAPs choreograph cellular signaling from the membrane to the nucleus. Trends Cell Biol 25(3):171–184 Thines L, Li Z, Sacks DB (2023) IQGAP1 Is a Phosphotyrosine-Regulated Scaffold for SH2-Containing Proteins. Cells 12(3):483 Rotoli D, Morales M, Maeso MD, Ávila J, Pérez-Rodríguez ND, Mobasheri A, van Noorden CJF (2019) Martín-Vasallo P. IQGAP1, AmotL2, and FKBP51 Scaffoldins in the Glioma Microenvironment. J Histochem Cytochem 67(7):481–494 Additional Declarations No competing interests reported. Supplementary Files TableS1.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4192532","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":286468764,"identity":"791b6948-8ab5-4655-9c8c-496358e1834e","order_by":0,"name":"Fuguang Zhang","email":"","orcid":"","institution":"First Affiliated Hospital of Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Fuguang","middleName":"","lastName":"Zhang","suffix":""},{"id":286468766,"identity":"0c375f84-139b-4c1f-82cf-ed323aeed74b","order_by":1,"name":"Heng Wang","email":"","orcid":"","institution":"Shenzhen Second People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Heng","middleName":"","lastName":"Wang","suffix":""},{"id":286468767,"identity":"68d000a7-f2e1-47a3-844e-81f1f103dfb5","order_by":2,"name":"Weiqian Zheng","email":"","orcid":"","institution":"Shantou University Medical College：Shantou City","correspondingAuthor":false,"prefix":"","firstName":"Weiqian","middleName":"","lastName":"Zheng","suffix":""},{"id":286468768,"identity":"6d1c7502-0d4a-4607-b618-30426c376ea1","order_by":3,"name":"Dinghao Wang","email":"","orcid":"","institution":"First Affiliated Hospital of Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Dinghao","middleName":"","lastName":"Wang","suffix":""},{"id":286468769,"identity":"dbe5e9cf-8d23-40db-81db-2a21deded78f","order_by":4,"name":"Chuangnan Yan","email":"","orcid":"","institution":"First Affiliated Hospital of Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Chuangnan","middleName":"","lastName":"Yan","suffix":""},{"id":286468770,"identity":"435e6bda-8d76-404a-b705-202c24bef882","order_by":5,"name":"Shuxin Chen","email":"","orcid":"","institution":"First Affiliated Hospital of Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Shuxin","middleName":"","lastName":"Chen","suffix":""},{"id":286468771,"identity":"a9454ecc-862c-416b-bfe7-1e6929d0b2f8","order_by":6,"name":"Hongwu Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAg0lEQVRIiWNgGAWjYBACAxDxgWQtjDNI1sLMQ5IWc4kcM2mbMmsG/vbuBOK0WM5IS5POOZfOIHHm7AYiHXY7+Zh0btthBgOJXKK1JLZJW5KoBWgLI2la7j9Ltuw5l85Dgl/OnDG88aPMWo6/vZdILRDARmLUgLWQqmMUjIJRMApGEgAAB/QoAelJDggAAAAASUVORK5CYII=","orcid":"","institution":"First Affiliated Hospital of Shantou University Medical College","correspondingAuthor":true,"prefix":"","firstName":"Hongwu","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2024-03-30 13:59:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4192532/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4192532/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54312926,"identity":"f50a4aa3-ab54-4caa-8ef6-9be33848fd58","added_by":"auto","created_at":"2024-04-08 17:25:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":573035,"visible":true,"origin":"","legend":"\u003cp\u003eWorkflow diagram of this paper.\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/81b9b5e5bfc5d8571e134605.png"},{"id":54311772,"identity":"fc6c0727-1378-4c27-8bc4-84773f7b6a94","added_by":"auto","created_at":"2024-04-08 17:17:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":685812,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of lncRNAs associated with disulfidptosis.（A）Network diagram of lncRNAs associated with disulfidptosis.（B）LASSO coefficient curve for lncRNAs associated with disulfidptosis.（C）Ten-fold cross-validation for parameter selection in the LASSO model.（D）Support vector machine recursive feature elimination (SVM-RFE) algorithm.（E）Venn diagram of two machine learning algorithms.（F）Receiver operating characteristic (ROC) curve of lncRNAs associated with disulfidptosis.（G）Multivariate Cox analysis visualizationof lncRNAs associated with disulfidptosis.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/27bcc2c30508e884432a1045.png"},{"id":54312925,"identity":"80a5943e-9c2c-4833-8d8b-84fc31d51a9c","added_by":"auto","created_at":"2024-04-08 17:25:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":288287,"visible":true,"origin":"","legend":"\u003cp\u003eExpression of LINC01842 among different subgroups. (A) Expression of LINC01842 in different genders. (B) Expression of LINC01842 in different age groups. (C) Expression of LINC01842 in different malignancy grades of glioma.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/3fbaca0ed29b5a687ed840d6.png"},{"id":54311773,"identity":"87279915-7d64-4f47-9327-50516d3f6ac9","added_by":"auto","created_at":"2024-04-08 17:17:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":420862,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curve analysis dependent on LINC01842 expression in different subgroups. (A, B) Survival difference between high- and low- LINC01842 patients of different genders. (C, D) Survival difference between high- and low- LINC01842 patients in different age groups. (E, F, G) Survival difference between high- and low- LINC01842 patients of different malignancy grades of glioma.\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/d62fadd26f3930fa67f05c67.png"},{"id":54311775,"identity":"1cbe436a-0112-49ea-8cbd-d4a498001cb1","added_by":"auto","created_at":"2024-04-08 17:17:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":698230,"visible":true,"origin":"","legend":"\u003cp\u003eBioinformatics analysis of LINC01842. (A) Regulatory element information of LINC01842.（B ,C）Structure and Function of LINC01842.（D）The nuclear-cytoplasmic distribution of LINC01842.（E）Expression of LINC01842 in normal tissues（F）Expression of LINC01842 in different tumors.\u003c/p\u003e","description":"","filename":"Fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/43f88ccc5aa8a02ad49f6231.png"},{"id":54311777,"identity":"18ec44d6-e9ad-4983-899e-e2e9775bac90","added_by":"auto","created_at":"2024-04-08 17:17:34","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1117903,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of LINC01842 on glioma. (A, C) Cell migration of U251 and LN229 cells was measured by wound healing assay. (B) Quantification of LINC01842 expression incell lines. (D) Cell viability of U251 and LN229 cells under microscope during 24-hour glucose deprivation. (E) Cell viability of U251 and LN229 during 24-hour glucose deprivation.\u003c/p\u003e","description":"","filename":"Fig.6.png","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/31f0af862049673743ee9bfc.png"},{"id":54312927,"identity":"e9e06d6a-8f78-4944-8179-081f1c2f8a9f","added_by":"auto","created_at":"2024-04-08 17:25:34","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":684468,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between LINC01842 and disulfidptosis. (A, B, C) Expression of LINC01842 in U251 and LN229 cells after 24 hours of glucose deprivation. (E, F, G) Expression of IQGAP1 in U251 and LN229 cells after 24 hours of glucose deprivation. (D, H) Expression of SLC7A11 in U251 and LN229 cells after 24 hours of glucose deprivation. (I) Expression of IQGAP1 in tumor tissues of different malignancy grades. (J) Quantification of IQGAP1 expression in U251 and LN229 cells.\u003c/p\u003e","description":"","filename":"Fig.7.png","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/0a3ee48591128f66f8e22773.png"},{"id":54311779,"identity":"80f58d4c-ac3f-438a-8959-c7de699a9792","added_by":"auto","created_at":"2024-04-08 17:17:34","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":1855569,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between LINC01842 and IQGAP1. (A) Correlation analysis of LINC01842 and IQGAP1. (B) Correlation analysis of LINC01842 and SLC7A11. (C) Prediction of binding sites between LINC01842 and IQGAP.\u003c/p\u003e","description":"","filename":"Fig.8.png","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/b41305aedba1c06e0ea34320.png"},{"id":54311781,"identity":"7667cac1-0d05-4181-a03e-abe306f97119","added_by":"auto","created_at":"2024-04-08 17:17:34","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":273522,"visible":true,"origin":"","legend":"\u003cp\u003eHigh-LINC01842 patients may more sensitive to chemotherapy. (A) LINC01842’s relationship with drug IC50 values. (B–F) Comparison of the IC50 value of AZD2014 (B), Entospletinib (C), PLX-4720 (D), Rapamycin (E) and SCH772984 (F) between high- and low-LINC01842 patients.\u003c/p\u003e","description":"","filename":"Fig.9.png","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/dac667b1341dba7f4bc281cb.png"},{"id":66897850,"identity":"4979e8dc-d2c1-469d-abed-7628903717b1","added_by":"auto","created_at":"2024-10-17 15:46:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7500310,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/ba1c62d5-4710-481a-a39a-a665c771ee39.pdf"},{"id":54311782,"identity":"2547c162-d611-49b6-b8a7-a941aede864a","added_by":"auto","created_at":"2024-04-08 17:17:35","extension":"xlsx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":9093,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4192532/v1/37000fb4bbd63557a5e41fd3.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eLong noncoding RNA LINC01842 enhances disulfidptosis resistance and promotes glioma progression via IQGAP1\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlioma is a malignant brain tumor with highly invasive and treatment-resistant properties (Venkataramani V et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Gliomas are characterized by the formation of abundant new blood vessels and unusual vascular structures, which often lead to resistance against conventional treatments, such as radiotherapy and chemotherapy, resulting in tumor recurrence and poor prognosis (Ahir BK et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Yang H et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Ma W et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Traditional treatment options, such as surgical resection, radiotherapy, and chemotherapy, can alleviate symptoms and control tumor growth to some extent (Su X et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Kim Y et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Tsien CI et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). However, not all patients experience ideal treatment outcomes with these approaches (Wang C et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Therefore, it is crucial to explore new therapeutic strategies to improve the treatment effectiveness of glioma.\u003c/p\u003e \u003cp\u003eRecent studies have revealed that in cells with high expression of the SLC7A11 gene, when they encounter glucose starvation, there is an abnormal accumulation of cysteine and other disulfides within the cells, leading to disulfide stress (Liu X et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). This process triggers an increase in the content of disulfide bonds in the actin cytoskeleton, causing contraction of actin filaments and disruption of the cytoskeletal structure, ultimately resulting in cell death (Liu X et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). This cell death pathway is known as disulfidptosis, which is distinct from apoptosis and ferroptosis (Zheng T et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Currently, research on disulfidptosis is still in its early stages and mainly focuses on a few types of tumors. For instance, studies have found that multiple disulfidptosis-related genes, such as LRPPRC, OXSM, GYS1, and SLC7A11, are associated with prognosis in patients with renal clear cell carcinoma (Zhang D et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Additionally, research by Zhang et al. suggests that disulfidptosis-related genes, such as KIF20A, G6PD, SLC7A11, and SLC2A1, play a role in the development of liver cancer (Zhang C et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Moreover, it has been reported that a combination of disulfidptosis-related genes, such as EPHX1, LDHA, SHC1, MYO6, and TLE1, can predict the clinical prognosis of patients with lung adenocarcinoma (He D et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough the relationship between disulfidptosis and glioma progression has not been reported, the aggressive proliferative nature of glioma leads to inadequate blood supply to the tumor tissue (Truong D et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kim Y et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), making the tumor cells susceptible to glucose starvation (Chisari A et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Teramoto K et al., 2019). As mentioned above, glucose starvation triggers an increase in the content of disulfide bonds in cell, causing contraction of actin filaments and disruption of the cytoskeletal structure, ultimately resulting in disulfidptosis (Liu X et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). This suggests a potential, as yet unknown connection between glioma development and disulfidptosis. However, further research is needed to explore their relationship.\u003c/p\u003e \u003cp\u003eLong non-coding RNA (lncRNA) is a class of RNA molecules that are widely present in cells (Ahmadpour ST et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Hasenson SE et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). They are usually longer than 200 nucleotides and do unable to transform proteins (Nojima T et al., 2022). Recent studies have shown that lncRNAs play a significant role in the formation and development of glioma through gene regulation and epigenetic modifications (Li Z et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). For example, high expression of lncRNA HOTAIR in high-grade gliomas is associated with lower survival rates (Wang X et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Additionally, it has been reported that lncRNA GAS5 inhibits glioma maintenance through a miR-196a-5p/FOXO1 feedback loop (Zhao X et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Moreover, FOXM1-AS has been found to facilitate the interaction between ALKBH5 and newly transcribed FOXM1, leading to the activation and progression of glioma (Zhang S et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). However, the regulation of lncRNAs in disulfidptosis in glioma is not yet clear.\u003c/p\u003e \u003cp\u003eIn this study, we identified a 785 nt long non-coding RNA1842 (LINC01842, ENSG00000267147), that was highly expressed in high-grade gliomas tissues and patients with high expression levels of LINC01842 had worse survival prognosis. Besides, tumor cells with high expression of LINC01842 have stronger tumor characteristics, such as migration and disulfidptosis resistance. Furthermore, In our study, we revealed that LINC01842 exerted its disulfidptosis resistance through interaction with IQGAP1.Our research findings provide evidence for the involvement of LINC01842 in glioma and offer new insights for personalized and precise treatment strategies for this disease.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAcquisition of datasets and disulfidptosis-related lncRNA\u003c/h2\u003e \u003cp\u003eThe RNA-seq transcriptome data for glioblastoma (GBM) and lower grade glioma (LGG) were downloaded from The Cancer Genome Atlas (TCGA) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://portal.gdc.cancer.gov/\u003c/span\u003e\u003cspan address=\"https://portal.gdc.cancer.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and all data was normalized to TPM (transcripts per million) value. In addition, the clinical information involving age, sex and grade was collected. Samples missing survival information were excluded. In all, a total of 709 samples were filtered for the study. Fifteen disulfidptosis-related genes (DRGs) were included based on a previous study: FLNA, FLNB, MYH9, TLN1, ACTB, MYL6, MYH10, CAPZB, DSTN, IQGAP1, ACTN4, PDLIM1, CD2AP, INF2, SLC7A11 (Wang T et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Using these target genes, we screened 545 disulfidptosis-related lncRNAs (DRLs) by person correction analysis. Correlations with a correlation coefficient absolute value of \u0026gt;\u0026thinsp;0.5, and corresponding to a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered eligible.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eIdentification of LINC01842 as a key prognosis-related gene\u003c/h2\u003e \u003cp\u003eFirstly, we obtained 331 prognostic DRLs by using univariate cox regression analysis. Secondly, the LASSO and SVM-RFE algorithms were used to choose the putative prognostic DRLs. Six common lncRNAs were filtered by integrated analysis of two algorithms. Thirdly, five lncRNAs were identified as independent prognosis lncRNAs. Among the genes, AL592295.6 was a protective gene, whereas AC064875.1, AC131097.3, MIR155HG, LINC01842 were risk genes. Subsequently, the R package \u0026ldquo;pROC\u0026rdquo; was leveraged to perform a ROC curve. The area under the ROC curve of the LINC01842 was 0.7821. Thus, we selected LINC01842 for further analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDrug response prediction\u003c/h2\u003e \u003cp\u003ePharmacogenomic data from Genomics of Drug Sensitivity in Cancer (GDSC) includes the therapeutic sensitivity of cancer cells and molecular markers of drug response (Yang W et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). The R package \u0026ldquo;oncoPredict\u0026rdquo; was used to calculate the half maximal inhibitory concentration (IC50) value, which is an indicator of drug sensitivity (Maeser D et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCell culture\u003c/h2\u003e \u003cp\u003eTwo human glioma cell lines (U251 and LN229) were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Both cell lines were cultured in Dulbecco\u0026rsquo;s modified Eagle\u0026rsquo;s medium (DMEM, Gibco BRL, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (Gibco BRL, Grand Island, NY, USA) and antibiotics (100 U/mL penicillin and 100 \u0026micro;g/mL streptomycin, Gibco, Grand Island, NY, and Scotland, UK) at 37\u0026deg;C in a humidified atmosphere containing 5% CO2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCell counting kit-8 (CCK8) assay\u003c/h2\u003e \u003cp\u003eCells of each group were inoculated at a density of 1\u0026times;10\u003csup\u003e4\u003c/sup\u003e cells/well in a 96-well plate, with 6 replicate wells for each group. After 24 hours, cell viability was measured by adding 10 \u0026micro;L of CCK8 reagent (Beyotime, Jiangsu, China)/well and incubating for 3 hours in a CO2 incubator. Cell viability was determined at the wavelength of 450 nm.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eQuantitative real-time PCR (qPCR)\u003c/h2\u003e \u003cp\u003eQuantitative real-time polymerase chain reaction (qRT-PCR) was performed. Total RNA was extracted from human tissues and cultured cells using TRIzol reagent (Takara, Shiga, Japan). Subsequently, cDNA was generated using a reverse transcription kit (Takara, Shiga, Japan), and gene expression was quantified using a SYBR Green PCR kit (Takara, Shiga, Japan) according to the manufacturer\u0026rsquo;s instructions. The primer sequences are listed in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eGlucose deprivation\u003c/h2\u003e \u003cp\u003eWe seeded glioma cells onto a 6-well cell culture plate (Corning, NY, USA) and allowed the cells to grow to approximately 90% confluence. The cell culture media was then replaced with glucose-free DMEM. After continuous cultivation for 24 hours, RNA extraction was performed for further analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eWound healing assay\u003c/h2\u003e \u003cp\u003eTo assess the migration and invasion of glioma cells in vitro, we performed a wound healing assay. Glioma cells were seeded onto a 6-well cell culture plate (Corning, NY, USA). Using a 200 \u0026micro;L pipette tip, a vertical scratch was made at the center of each well. The cells were then cultured in DMEM media without fetal bovine serum (FBS) for 24 hours. Images were captured under a 10x microscope objective. The gap area was measured using ImageJ software\u0026rsquo;s ruler tool. Changes in the gap area were calculated and analyzed using statistical methods.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error of the mean (SEM). Statistical analysis was performed using R language (version 3.5), SPSS 25.0 software (SPSS Inc., Chicago, Illinois) or GraphPad Prism 7 (GraphPad software, La Jolla, CA). The R package \u0026ldquo;survminer\u0026rdquo; was used to estimate OS between two groups using Kaplan-Meier survival plots. Cox regression of survival analysis was implemented by the R package \u0026ldquo;survival\u0026rdquo;. Related R packages, including \u0026ldquo;ggplot2\u0026rdquo; and \u0026ldquo;ggpubr\u0026rdquo;, were used to visualize the data. Differences with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eIdentification of disulfidptosis-related lncRNAs using TCGA\u003c/h2\u003e \u003cp\u003eThe workflow in the current study is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. To explore the role of lncRNAs associated with disulfidptosis in glioma, we first screened 545 disulfidptosis-related lncRNAs (DRLs) by person correction analysis and constructed a gene network map (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). An absolute value of correlation coefficients\u0026thinsp;\u0026gt;\u0026thinsp;0.5 corresponding to a \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/em\u003e was considered eligible for consideration. Next, we obtained RNA-seq data from 709 samples in TCGA. Considering that traditional Cox regression analysis often ignores multicollinearity between variables when dealing with multiple gene variables, which may lead to inaccurate results, we used LASSO regression analysis to identify lncRNAs associated with prognosis. The results showed that 25 lncRNAs were significantly correlated with prognosis (cor_thred\u0026thinsp;=\u0026thinsp;0.5, p value_thred\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). We performed 10-fold cross-validation to determine the optimal value of the penalty parameter (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Additionally, we used the support vector machine recursive feature elimination (SVM-RFE) algorithm for machine learning feature selection, and identified 11 prognosis-related lncRNAs (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). We then performed Venn diagram analysis on the results of these two machine learning algorithms to obtain their intersection. Last, we selected 6 lncRNAs, LINC01842, AL592295.6, AC131097.3, MIR155HG, CYTOR, and AC064875.1, as prognostic risk factors for glioma (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). To further explore the independent prognostic impact of each lncRNA, we conducted receiver operating characteristic (ROC) curve analysis and stepwise regression multivariate Cox regression analysis. The results showed that their predictive efficacy for glioma prognosis was high, with AUC values greater than 0.7 (AL592295.6\u0026thinsp;=\u0026thinsp;0.77, AC131097.3\u0026thinsp;=\u0026thinsp;0.785, MIR155HG\u0026thinsp;=\u0026thinsp;0.763, LINC01842\u0026thinsp;=\u0026thinsp;0.7821, CYTOR\u0026thinsp;=\u0026thinsp;0.79102, AC064875.1\u0026thinsp;=\u0026thinsp;0.76075) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF). However, only 5 lncRNAs served as independent prognostic factors for glioma: LINC01842, AL592295.6, AC131097.3, MIR155HG, and AC064875.1(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG). Particularly noteworthy is that LINC01842 is considered an oncogene, and it has the highest hazard ratio and a highly significant p-value (HR\u0026thinsp;=\u0026thinsp;1.377, \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/em\u003e), indicating that LINC01842 may be closely associated with poor prognosis in glioma patients. Therefore, we further investigated and analyzed LINC01842 in detail.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAge and malignancy grade of glioma may affect the expression of LINC01842\u003c/h2\u003e \u003cp\u003eTo study the association between LINC01842 and the prognosis of glioma, we analyzed the expression of this gene in different subgroups, including gender, age (\u0026lt;\u0026thinsp;60 years or \u0026ge;\u0026thinsp;60 years), and malignancy grade of glioma (WHO: G2, G3, G4). We found that expression of LINC01842 did not differ significantly between genders (\u003cem\u003eP\u0026thinsp;=\u0026thinsp;0.7935\u003c/em\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA), but there were significant differences in its expression levels among different age groups and malignancy grades of glioma (\u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/em\u003e). Notably, LINC01842 expression was higher in patients over 60 years of age and those with high-grade gliomas (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, C). These results suggest that the age and tumor malignancy of patients may affect the expression of LINC01842. Additionally, other studies have reported that the expression of LINC01842 is higher in lymph node metastasis patients than in non-metastasis patients with non-small cell lung cancer (Wang X et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), which is consistent with our findings.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eGlioma patients with high expression of LINC01842 exhibit poorer clinical prognosis\u003c/h2\u003e \u003cp\u003eTo eliminate the interference of age and tumor malignancy grade on LINC01842expression level, we grouped patients based on high or low expression levels of LINC01842 under different conditions of gender, age, and tumor malignancy grade, and analyzed the impact of LINC01842 on the survival rate of glioma patients. Interestingly, we found a consistent phenomenon across different gender, age, and tumor malignancy grade conditions: patients with high expression levels of LINC01842 had worse survival prognosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This suggests that although age and tumor malignancy grade can affect the expression level of LINC01842, LINC01842 is the major factor affecting the prognosis of glioma. Therefore, there may be a close association between LINC01842 and the occurrence and development of glioma.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eBiological information of LINC01842\u003c/h2\u003e \u003cp\u003eTo investigate the relationship between LINC01842 and the development of glioma, we first analyzed the genomic information of LINC01842 using the UCSC Genome database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://genome.ucsc.edu/\u003c/span\u003e\u003cspan address=\"https://genome.ucsc.edu/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). We found that LINC01842 is a conserved and abundant lncRNA, currently annotated as LINC01842 in humans. It is located on chromosome 19p13.12 on the coding strand. The gene sequence can produce two transcripts: NR_134916.1 and NR_134908.1. Additionally, high levels of regulatory element markers, such as cCREs and CpG islands, were detected for LINC01842 (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). These results suggest that LINC01842 possesses enhancer activity rather than coding activity. Although genetic information is encoded in the RNA sequence, lncRNA activity depends on the RNA folding into specific secondary or tertiary structures. A well-known example is ribosomal RNA, which forms complex tertiary structures and catalyzes protein synthesis during translation (H\u0026auml;fner SJ et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Using the lncRNA-related functionality database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi\u003c/span\u003e\u003cspan address=\"http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), we further analyzed the structure and function of LINC01842. The analysis revealed the presence of multiple stable stem-loop structures in LINC01842 (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB, C). These structures may have binding or catalytic roles with proteins. Moreover, the analysis results showed that LINC01842 is predominantly located in the cytoplasm (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eD), suggesting that this gene may participate in gene regulation at the post-transcriptional level. For example, LUCAT1 competes for binding with miR-375 in the cytoplasm to regulate the proliferation and invasion of glioma cells (Gao YS et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Furthermore, we discovered through the NONCODE database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.noncode.org/\u003c/span\u003e\u003cspan address=\"http://www.noncode.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) that LINC01842 is primarily expressed in normal lung tissues (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eE). However, LINC01842 is predominantly overexpressed in highly malignant tumors, such as invasive breast cancer, renal clear cell carcinoma, and lung squamous cell carcinoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eF).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eTumor cells with high expression of LINC01842 exhibit more invasive\u003c/h2\u003e \u003cp\u003eTo further investigate the mechanism of LINC01842 in the development of tumors, we cultured two glioma cell lines (U251 and LN229) and determined the expression level of LINC01842. Compared to LN229 cells, LINC01842 was expressed at a higher level in U251 cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB). Based on our bioinformatics analysis and prior studies (Wang X et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), tumor cells with high expression of LINC01842 may have more invasive. Furthermore, to compare the invasion ability of U251 and LN229 cell lines, we performed wound healing assays on the two cell lines. a U251 cells had a faster wound healing rate (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA, C), suggesting that U251 cells had greater migration abilities. Additionally, according to previous reports (Liu X et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), we induced cell death in both cell lines by treating them with glucose deprivation for 24 hours. We found that U251 cells had higher cell viability than LN229 cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eD, E), and the expression levels of SLC7A11, a critical gene in disulfidptosis (Liu X et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), were increased in both cell lines after treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eD, H). This may indicate that U251 cells have a stronger tolerance to disulfidptosis. In summary, our experimental data and bioinformatics analysis mutually support the notion that tumor cells with high expression of LINC01842 are more invasive, such as migration and disulfidptosis resistance. These results show that LINC01842 may be positively correlated with the malignancy of tumors.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eGlioma cells with high expression of IQGAP1 have stronger disulfidptosis tolerance\u003c/h2\u003e \u003cp\u003eAccording to previous reports in the literature, when cells are deprived of glucose, cytoskeleton collapse and plasma membrane separation occur, ultimately leading to cell death, known as disulfidptosis (Liu X et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). In addition, LINC01842 was predicted to be associated with IQGAP1, an intracellular actin-binding protein that can maintain cytoskeleton stability and regulate various cellular activities by promoting intracellular signal transduction (Thines L et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Therefore, we focused on the role of IQGAP1 in glioma. In our study, we found that expression of IQGAP1 was higher in U251 cells than in LN229 cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eJ). Online immunohistochemical analysis (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"https://portal.gdc.cancer.gov/\" target=\"_blank\"\u003ewww.proteinatlas.org\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.proteinatlas.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) also showed that the expression of IQGAP1 was higher in tissues with high-grade gliomas and lower in tissues with low-grade gliomas (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eI). This indicates that the expression level of IQGAP1 may be related to the malignant degree of tumors. Our experimental results (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA, C, D, E) are consistent with the study by Zhang et al., which showed that high expression of IQGAP1 enhances the migration and invasion of neuroglioma (Zhang Q et al., 2019). In addition, we induced a cell model of disulfidptosis by subjecting the above two cell lines to glucose deprivation for 24 hours. After treatment, the expression levels of IQGAP1 increased in both cell lines (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eE, F). Interestingly, the expression level of IQGAP1 in U251 cells was consistently higher than that in LN229 cells before and after glucose deprivation (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eG), and the expression of LINC01842 also showed consistent changes with IQGAP1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eA, B, C). Combined with the stronger tolerance of U251 cells compared with LN229 cells, we postulate that U251 cells may exhibit disulfidptosis resistance by maintaining cytoskeleton stability by overexpressing IQGAP1. In summary, our data indicate that glioma cells with high expression of IQGAP1 have stronger disulfidptosis tolerance.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eLINC01842 participates in disulfidptosis through IQGAP1\u003c/h2\u003e \u003cp\u003eTo further investigate the cellular regulatory mechanisms of LINC01842, IQGAP1, and SLC7A11, we conducted a correlation analysis between them by their expression levels. The results revealed a positive correlation between the expression levels of LINC01842 and IQGAP1 (R\u0026thinsp;=\u0026thinsp;0.51, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eA), but no significant correlation between LINC01842 and SLC7A11 expression levels (R\u0026thinsp;=\u0026thinsp;0.07, P\u0026thinsp;=\u0026thinsp;0.08) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eB). This suggests that LINC01842 may primarily influence the expression of IQGAP1, leading to the development of resistance to disulfidptosis. To explore the potential interaction between LINC01842 and IQGAP1, we utilized an online analysis tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://service.tartaglialab.com/\u003c/span\u003e\u003cspan address=\"http://service.tartaglialab.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to predict their potential binding sites based on their secondary structure, hydrogen bonding, and van der Waals interactions. The results demonstrated a strong binding capability between LINC01842 and IQGAP1 (prediction using RF classifier\u0026thinsp;=\u0026thinsp;0.7, prediction using SVM classifier\u0026thinsp;=\u0026thinsp;0.78) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eC). This further supports the hypothesis that LINC01842 may promote resistance to disulfidptosis through its interaction with IQGAP1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eIdentification of potential drugs targeting LINC01842\u003c/h2\u003e \u003cp\u003eGiven that chemotherapy is also an effective method for the treatment of glioma (Le Rhun E et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), it has important clinical application value and prospects. Therefore, using the oncoPredict algorithm, we aimed to identify potential drugs that target LINC01842 and predict drug sensitivity in glioma patients. The results showed that there was a negative correlation between LINC01842 and IC50 values of 8 drugs (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eA). We selected the top 5 drugs with the strongest correlation to LINC01842 for analysis. These drugs, namely entospletinib (targeting drug, Syk inhibitor), AZD2014 (targeting drug, mTOR inhibitor), PLX-4720 (targeting drug, B-Raf inhibitor), rapamycin (targeting drug, mTOR inhibitor) and SCH772984 (targeting drug, ERK inhibitor), exhibited meaningfully lower IC50 values in the high-LINC01842 group than the low-LINC01842 group, which suggests that these drugs may bring greater benefits to patients in the high-LINC01842 group (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eB\u0026ndash;F).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eGlioma is a molecularly heterogeneous malignant tumor (Gusyatiner O et al., 2018), and the current main drug used for its treatment is TMZ, but its efficacy is limited (Corrigenda et al., 2017). Therefore, it is crucial to identify key biomarkers and therapeutic targets that influence prognosis in order to improve the clinical outcomes of glioma patients. In addition, disulfidptosis, as a mode of cell death similar to other cell death modes, plays an important role in the development of various types of tumors. For example, ferroptosis assists in overcoming gemcitabine resistance in pancreatic cancer (Kim MJ et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), and pyroptosis affects all stages of tumor carcinogenesis (Tan Y et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Studies have suggested that disulfidptosis-related genes, such as POU5F1 and CTSE, may be potential targets for treating bladder cancer (Chen H et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Moreover, the disulfidptosis-related gene G6PD can inhibit the proliferation of lung cancer cells (Qi C et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Therefore, we postulated that disulfidptosis-related genes (DRGs) may play a role in the occurrence and prognosis of glioma.\u003c/p\u003e \u003cp\u003eLong non-coding RNA (lncRNA) has been confirmed to play an important role in the prognosis of glioma and may serve as a potential molecular target for glioma treatment. Some studies have found that lncRNA NEAT1 promotes the development of glioma by stabilizing PGK1, and high expression of NEAT1 is associated with poor overall survival in patients (Liang J et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). In addition, mitochondrial ferritin promotes tumor occurrence and angiogenesis in glioma through the expression of long non-coding RNA SNHG1 (Mi S et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). However, the regulatory mechanism of disulfidptosis in glioma and its relationship with lncRNA still remain unclear. Therefore, it is necessary to focus on the interaction between disulfidptosis and lncRNA in order to identify effective prognostic markers.\u003c/p\u003e \u003cp\u003eFirst, we predicted lncRNAs associated with disulfidptosis based on 14 ferroptosis-related genes (DRGs), and constructed a network of disulfidptosis-related genes. Then, we obtained RNA-seq data of glioma tissue from TCGA and used a series of bioinformatics analyses to screen our target gene LINC01842. LINC01842 was found to be an oncogene, as it had the highest hazard ratio and a significant p-value, suggesting a strong association with poor prognosis in glioma patients. Currently, there is limited research on LINC01842 in the context of cancer treatment. To our knowledge, there are only two reported studies on LINC01842. One study constructed a competing endogenous RNA (ceRNA) network centered around LINC01842 and other long non-coding RNAs to guide the diagnosis and prognosis of lung adenocarcinoma (Wang X et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Another study found a correlation between LINC01842 and tumor immunity as well as clinical prognosis in glioma (Chen F et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Our study also revealed that glioma patients with high expression of LINC01842 have worse clinical outcomes, and glioma cell lines with high expression of LINC01842 exhibit stronger tumor characteristics, such as invasiveness, proliferation, and resistance to disulfidptosis.\u003c/p\u003e \u003cp\u003eIQ motif containing GTPase activating protein 1 (IQGAP1) is a large, widely expressed protein with a size of 190 kDa (Weissbach L et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e1994\u003c/span\u003e). IQGAP1 belongs to the IQGAP protein family and is evolutionarily conserved in eukaryotes (Abel AM et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Hedman AC et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). It was first identified in 1994 and initially believed to be a GTPase activating protein (GAP) that promotes signal termination based on its sequence similarity to other known GAPs (Weissbach L et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e1994\u003c/span\u003e). However, subsequent studies revealed that IQGAP1 does not shut down signals but rather stabilizes the activity of binding partners such as RAC1 and CDC42 by inhibiting their intrinsic GTPase activity (Hart MJ et al., \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e1996\u003c/span\u003e). Research has demonstrated that this protein is involved in various biological activities, including cell cytoskeleton dynamics, cell-cell adhesion, cell motility/invasion, and cell proliferation (Tanos BE et al., 2016; Smith JM et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Thines L et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Rotoli D et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Our study found that there is a binding site between LINC01842 and IQGAP1, and their expression levels are positively correlated. To further investigate the relationship between LINC01842 and IQGAP1, we conducted in vitro experiments such as cell scratch assays, cell viability assays, and glucose deprivation, using two glioma cell lines (U251 and LN229). The results showed that the cell line with higher expression of LINC01842 (U251 cells) also exhibited higher expression of IQGAP1 and demonstrated increased resistance to disulfidptosis. Therefore, we propose that U251 cells may enhance their resistance to disulfidptosis by maintaining cytoskeletal stability through the upregulation of IQGAP1.\u003c/p\u003e \u003cp\u003eIn addition, we also predicted the drug sensitivity of glioma patients and found that patients with high expression of LINC01842 should be sensitive to entospletinib, AZD2014, PLX-4720, rapamycin and SCH772984. This evidence may further guide the chemotherapy and targeted therapy of glioma.\u003c/p\u003e \u003cp\u003eIt should be noted that we did not choose to conduct in vitro experiments on normal astrocytes for multiple reasons. Firstly, our study focused mainly on investigating the effect of LINC01842 on tumor characteristics of glioma cells, such as invasion, proliferation, and resistance to disulfidptosis. Secondly, in the process of screening LINC01842, we did not analyze the expression levels of this gene in normal astrocytes, but rather compared its expression levels in glioma samples of different degrees of malignancy. Finally, we found that there were expression differences of LINC01842 between the U251 and LN229 glioma cell lines. Therefore, using these two cell lines for in vitro experiments provides us with a better understanding of the role of LINC01842 in glioma.\u003c/p\u003e \u003cp\u003eHowever, our study still has certain limitations: (1) most of the data are derived from the public database TCGA and lack sufficient experimental evidence and animal models to validate the results, which may cause potential selection bias, (2) the sensitivity of glioma tissue to chemotherapy and targeted drugs is yet to be verified, and (3) the specific mechanism of disulfidptosis remains relatively mysterious and deserves further investigation. Therefore, we will carry out multiple studies in the future to further explore the molecular relationship between LINC01842 and disulfidptosis in glioma.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, our study showed that LINC01842 was able to promote tumor growth and metastasis of glioma both in bioinformatics analysis and in vitro experiments. Mechanistically, we demonstrated that LINC01842 could interact with IQGAP1 to promote resistance to disulfidptosis of glioma. Moreover, using OncoPredict, we found that glioma patients with high expression level of LINC01842 were sensitive to eight drugs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eFZ and HW contributed to the study design and wrote the article. WC and DW conducted the literature search. CY and SC acquired the data. HX revised the article and gave the fnal approval of the version to be submitted.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthical Statement\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThis declaration is not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e \u003cstrong\u003eStatement\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThe study was funded by two grants\u003cstrong\u003e\u0026nbsp;:\u0026nbsp;\u003c/strong\u003eteaching Reform Research Program of Clinical Teaching Base of Guangdong Province,\u0026nbsp;〔2022〕21-2021JD066 and the Medical Scientific Research Foundation of Guangdong Province of China, Grant No. A2022176.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eThe data that support the findings of this study are available on request from the corresponding author, Hongwu Xu，upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eAll authors declare that they have no confict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVenkataramani V, Yang Y, Schubert MC, Reyhan E, Tetzlaff SK, Wi\u0026szlig;mann N et al (2022) Glioma hijacks neuronal mechanisms for brain invasion. 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J Histochem Cytochem 67(7):481\u0026ndash;494\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"glioma, disulfidptosis, LINC01842, IQGAP1, SLC7A11","lastPublishedDoi":"10.21203/rs.3.rs-4192532/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4192532/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eLong non-coding RNA (lncRNA) is widely present in cells and is demonstrated to play vital roles in the development and progression of glioma. However, the biological roles and function mechanisms of LINC01842 in glioma are not yet clear. This study aims to elucidate the potential role of LINC01842 in glioma, specifically its association with disulfidptosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We obtained sequencing data from The Cancer Gene Atlas (TCGA). Correction analysis was applied to select disulfidptosis-related lncRNAs (DRLs). Prognosis-associated DRLs were identified by least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM). Receiver operating characteristic (ROC) curve and multivariate Cox regression analyses were used to screen our target gene LINC01842. Subsequently, expression of LINC01842, IQGAP1and SLC7A11 in glioma cell lines was detected by real-time quantitative polymerase chain reaction (qPCR). Additionally, CCK8 experiments and wound healing assays were performed to assess cell viability, migration, and invasion. Finally, online database predictions were used to validate the drug sensitivity of glioma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eLINC01842 was more highly expressed in high-grade gliomas, and glioma patients with high expression level of LINC01842 had poorer survival. Additionally, tumor cells with high expression of LINC01842 exhibited stronger tumor characteristics, such as migratory and invasive abilities, as well as tolerance to disulfidptosis. Furthermore, strong binding between LINC01842 and the disulfidptosis-related gene IQGAP1 could be predicted, and their expression levels were positively correlated. Ultimately, drug sensitivity analysis suggested glioma patients with high expression level of LINC01842 were sensitive to eight drugs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eHigh expression of LINC01842 is associated with poor prognosis in glioma patients. By interacting with IQGAP1, the resistance to disulfidptosis of LINC0182 was stronger in glioma, which promotes the progression of glioma. Eight discovered sensitive drugs provided important clues for personalized treatment of glioma.\u003c/p\u003e","manuscriptTitle":"Long noncoding RNA LINC01842 enhances disulfidptosis resistance and promotes glioma progression via IQGAP1","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-08 17:17:29","doi":"10.21203/rs.3.rs-4192532/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4c4193fb-5a9c-4f9a-9a97-9c14e69ce420","owner":[],"postedDate":"April 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-17T15:38:42+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-08 17:17:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4192532","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4192532","identity":"rs-4192532","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}